The amino acid glutamate is an excitatory neurotransmitter that is an agonist at many post-synaptic terminals of the central nervous system. The glutamate receptor complex is termed the NMDA receptor and is a potential target for therapeutic drugs. This receptor incorporates an ion channel complex which is novel because it is gated by both dual ligand binding (glutamate and glycine) and membrane voltage. Because of the novel requirements for activation, it is believed that the NMDA receptor complex plays only a minor role in routine synaptic transmission. However, the receptor complex may be activated following repeated afferent stimuli as occurs during trauma such as surgery. Repeated stimuli cause a temporal summation of C-fibre-mediated responses of dorsal horn nociceptive neurones; this phenomenon, increased output to a constant input, is known as wind-up.
Studies indicate that activation of the NMDA receptor complex in the spinal dorsal horn leads to increased spontaneous neural discharge, expanded receptive fields and exaggerated responses to afferent input. These neural mechanisms may be expressed physically as hyperalgesia (increased pain sensation) and allodynia (pain arising from a stimulus that is not normally painful).
Opioids, through their ability to inhibit release of primary afferent neurotransmitters or to inhibit interneurons early in nociceptive pathways, initially reduce or block C-fibre inputs to the deeper dorsal horn nociceptive neurones. However, as the peripheral stimulation continues, wind-up breaks through the input inhibition and the neurones start to respond. Thus at moderate doses, opioids delay the onset of wind-up without inhibiting the process itself.
By contrast, NMDA receptor antagonists have no effect on the initial inputs to the cells but diminish or abolish wind-up and convert the potentiated response to a normal response.
We have found that a particularly effective composition for the administration of an NMDA receptor antagonist to diminish or abolish wind up is one providing both immediate release of an NMDA receptor antagonist and controlled or sustained release of an NMDA receptor antagonist.
NMDA antagonist receptors have also been indicated to be effective in the treatment of Huntington's disease, amyotrophic lateral sclerosis (ALS), AIDS-related dementia, Alzheimer's disease, schizophrenia, motoneurone diseases and CNS and brain injuries resulting from a number of causes including stroke, trauma and neurosurgery.